Preparation of 10beta-allyl steroids and intermediates



United States Patent PREPARATION OF IOB-ALLYL STEROIDS AND INTERMEDIATES Gerard Nomin, Noisy-le-Sec, Robert Bucourt, Clichysous-Rois, and Andr Pierdet, Noisy-le-Sec, France, assignors to Roussel-UCLAF, S.A., Paris, France, a corporation of France A I -No Drawing. Filed Feb. 19, 1963, Ser. No. 259,747

Claims priority, application France Feb. 24, 1962 9 Claims. (Cl. 260-2395) The present invention relates to a new process of preparation of lOfl-allyl steroids and the products obtained by this process. The present invention has more particularly for its object a new process of preparation of 10fl-allyl-A 9 -estradiene-17,8-01-3-one and its esters with organic carboxylic acids containing from 1 to 18 carbon atoms. These compounds are described in United States patent application Serial No. 83,381, filed January 18, 1961, now Patent No. 3,117,979.

As stated in co-pending United States patent application Serial No. 83,381, the said compounds are useful intermediates in steroidal synthesis, particularly in the production of .10/3-allyl-19-nor-adrenosterone and /3- allyl-19-nor cortisone. The process according to this patent application consists in ketalizing 17p-acyloxy-4,5-seco- A -estrene-3,5-dione in the 3-position, subjecting the ketalized product to an allylation in the. 10-position, transforming by hydrolysis the 3-monoketal of 17,8-acy1oxyl 0fi-allyl-4,5-seco-A -estrene-3,5-dione into 17,8-acyloxy-l0fi-allyl-4,5-seco-A -estrene-3,S-dione and cyclizing this latter compound with saponification by the action of an alkaline base into the, corresponding IOB-allyl- A -estradiene-17fi-o1-3-0ne.

An object of the present invention is the development of a new process for the production of a IOB-allyl steroid of the formula 3,132,138 Patented May 5, 1964 agent, subjecting the resultant 1OB-allyl-A -estrene-9a-ol 3,17-dione to the action of a dehydrating agent, blocking the 3 ketone group of the resultant 10/3-allyl-A estradiene-3,17-dione, subjecting the resultant steroid to the action of a reducing agent, freeing the blocked ketone in the 3-position and recovering said IOB-allyl steroid.

A further object of the invention is the production of the following intermediates:

1'0B-allyl-A -estrene-3 8,9 or, 17 ,B-triol 1O/3-a1lyl-A -estrene-9a-ol-3,17-dione l0fl-allyl-A -estradiene-3,17-dione 3-pyrrolidyl-10,8-al1yl-A ,5-9( -estratriene- 17-one 3-pyrrolidyllOfi-allyl-A -estratriene-UB-ol These and other objects of the invention will become more apparent as the description proceeds.

It has now been found that the allyl radical can be introduced with good yields into the IDs-position of a steroid by reaction of an allyl magnesium halide on the corresponding A -9a,10a-epoxy derivative according to the following flow diagram (only partially shown):

m x O U J Chem. and Ind., 1961, p. 1530).

prises the steps of reacting a compound of the formula wherein R is selected from the group consisting of hydrogen and the acyl radical of an organic carboxylic acid having from one to seven carbon atoms, with an allyl magnesium halide in an inert organic solvent, oxidizing the 3 3 and 175 hydroxyl groups of the resultant 1019- allyl-A -estrene-3fl,9a,l7fl-triol by means of an oxidizing The process of the invention consists essentially in that an allyl magnesium halide is made to react on ,100tr epoxy-A -estrene-3 3,l7fi-dio1 or the 17/3-ester of a lower carboxylic acid of the latter (II). The resultant 10,8- allylA -estrene-35,9u,17fi-triol (III), is subjected to the action of an oxidizing agent to oxidize the 3,8 and 17phydroxyl functions. 10 6-al1yl-A -estrene-9a-ol-3,17-dione (IV), is obtained which by the action of a dehydrating agent gives 10fi-allyl-A -estradiene-3,l7-dione (V). This compound is reduced, after having protected previously the ketone in the 3-position in the form of an enol ether or in the form of an enamine (VI), into the corresponding 17,6-hydroxylated derivative (VII), then by free ing the ketone in the 3-position, '10fl-a1lyl-A -estradiene-17,8-ol3-one (I), with R'=H, is obtained. This compound can be transformed, if desired, into any desired ester of compound I where R represents the acyl radical of an organic carboxylic acid having from one to eighteen carbon atoms. I

Table I is a flow diagram of the process of the invention.

TABLE I 1) The aforesaid table- The acyl radicals of an organic carboxylic acid having 1 to 18 carbon atoms are those of aliphatic or cycloaliphatic,saturated or unsaturated carboxylic. acids, or those of aromatic or heterocyclic carboxylic acids, for

example, alkanoic acids, such as formic acid, acetic acid,

propionic acid, butyric acid, isobutyric acid, vale'ric acid, isovaleric acid, trimethylacetic acid, caproic acid, ,B-trimethylpropionic acid, .enanthic acid, caprylic acid, pelarginic acid, capric acid, undecyclic acid, lauric acid,

myristic acid, palmitic acid, and stearic acid, alkenoic I acids, such as undecylenic acid'and oleic acid, cycloalkanoic acids, such as cyclopentyl-, cyclopropyl-, cyclobutyl-, and cyclohexylcarboxylic acids, cycloalkanealkanoic acids, such as cyclopropylmethylcarboxylic acid, cyclobutylmethylcarboxylic acid, cyclopentylethylcarboxylic acid, cyclohexylethylcarboxylic acid, aralkanoic acids, such as phenyl-acetic or propionic acids, benzoic acid, phenoxyalkanoic acids-such as phenoxyacetic acid, p-chlorophenoxyacetic acid, 2,4-dichlorophenoxyacetic acid, 4-t-butylphenoxyacetic acid, 3-pheuoxypropionic acid, 4-phenoxybutyric acid, furane-Z-carboxylic acid, 5-t-butylfurane-Z-carboxylic acid, S-bromofurane-Z-carboxylic'acid, nicotinic acids, B-ketocarboxylic acids, for

example, acetylacetic acid, propionylacetic acid, butyryl- 7 acetic acid, amino acids, such as diethylaminoacetic acid, aspartic acid, etc.

The introduction of the allyl group is eifectedby action of an allyl magnesium halide, preferably the bromide.

The reaction takes place in an inert organic .solvent'75 4 such as tetrahydrofuran or ether at temperatures from room temperature up to the reflux temperature.

The oxidizing agent used in order to oxidize the 3B and 17B hydroxyl groups of 10,8-allyl-A*-estrene-3,B,9a, 17fi-triol (III) is preferably an aqueous solution of sulfuric and chromic acids. The reaction takes place in an inert water-miscible organic solvent such as acetone at about room temperature.

The hydroxyl group in the t-POSitlOn of l0/8-allyl- A -estrene-9oz-ol-3,l7-dione (IV) is dehydrated preferably by the action of zinc chloride. The reaction takes place in an inert anhydrous organic solvent such as benzene at temperatures up to the reflux temperature. 7

The ketone function in the 3-position of 10,8-ally1- A -estradiene-3,l7-dione (V) is protected, preferably, by the preparation of its enamine, 3-pyrrolidyl- 10B-allyl-A -estratriene-17-one (VI). The reaction takes place by heating compound V with pyrrolidine up to the refluxing temperature.

The ketone in the l7-position of,3-pyrrolidyl--allyl- A -estratriene-17-0ne (VI) is reduced, preferably, with the aid of a mixed metal hydride such as lithium aluminum. hydride. The reactiontakes place in an inert anhydrous organic solvent at temperatures up to the refiux temperature. 7

The ketone in the 3-position of 3-pyrrolidyl-10p-allyl- A estratriene-17B-ol (VII) is liberated, preferably by hydrolysis of theenamine in an aqueous media containing acidic methanol. The reaction takes place by heating water, methanol and an organic carboxylic acid such as acetic acidat temperatures up to the reflux temperature.

In the. following examples there are illustrated several preferred embodiments to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments.

Example I PREPARATION OF 9a,10arEPOXY-IYfi-BENZOYLOXY-A ESTRENE-3B-OL 4.4 grams of 9a,l0oe-epoxy-17fi-benzoyloxy-A -estrene- 3-one having'a melting point of 173 C. and a specific rotation [o:.] =+112 (c.=1% in methanol) (obtained according to the process described. in US. Patent No. 3,055,885, issued September 25, 1962), were introduced into 1 8 cc. of tetrahydrofuran. 0.1 gram of sodium borohydride in 4 cc. of water was added under an atmosphere of nitrogen and the reaction mixture was agitated for a period of two hours at a temperature of 0. The mixture was concentrated to a small volume under vacuum. 20 cc. of water wereadded and'the mixture extracted with ether. The extracts, after washing with water and drying 'over sodium sulfate, furnished, after evaporation to dryness, 0.435 gram of raw 9a,10oc-epoxyl7fl-benzoyloxy-A -estrene-3B-ol which was purified by recrystallization from methanol and ethyl acetate.

The purified product had a melting point of 204.5 and a specific rotation [0L] =+116 (c. =0.5% in ethanol). The product occurred in the form of colorless prismatic needles, soluble in acetone, ethyl acetate and methanol.

Analysis.--C H O ,Molecular weight:394.5. Ca1- culated: C, 76.10%; H, 7.66%. Found: C, 76.0%; H, 7.5%.

Example 11 PREPARATION on meALLYL-AM -n'sTRAn1nNE-17a 01 (II, R=COC H prepared according to Example I, i

The -reaction mixture was agitated for a peroid of a quarter of an hour. Then 400 cc. of benzene were added thereto. The mixture was heated gently in such a fashion as to evaporate the ether and next the reaction mixture was maintained for one hour at reflux under an atmosphere of nitrogen. Thereafter the mixture was cooled in an ice bath and 300 cc. of an aqueous solutionof ammonium chloride were added thereto. The cooled mixture was extracted with ethyl ether. The extract was washed with water, dried and evaporated to dryness under vacuum. 4.6 gm. of raw 1Ofl-allyl-M estrene-35,90,17,8-triol (III) were obtained.

The raw product was taken up with methylene chloride and passed through a column containing 135 gm. of magnesium silicate gel (Florisil). The column was eluted by a solution containing 20% of acetone in methylene chloride and 2.90 gm. of a product were obtained after evaporation of the solvent. The product was dissolved in 40 cc; of acetone. 4 cc. of boiling isopropyl ether were added thereto and the solution was allowed to stand overnight at C.

The precipitate was vacuum filtered, washed with a mixture of acetone and isopropyl ether (1:1) and dried under vacuum.

1.10 gm. of 10fi-allyl-A -estrene-3fi,9a,17;8-triol (III) were'obtained having a melting point of 180 C. and a specific rotation [a] =+95.2 (c.=0.57% in methanol).; Yield: 49%.

This product is not described in the literature.

It occurs in the form of white needles, soluble in alcohol, acetone and ethyl acetate, insoluble in water and dilute aqueous acids and alkalis.

Analysis.C H O Molecular weight=332.47. Calculated: C, 75.85%; H, 9.70%. Found: C, 75.9%; H, 9.6%. t

Step B-1OB-allyl-M-estrene-9a-0l-3,17-di0n (IV) 0.440 gm. of 1OB-allyl-N-estrene-30,90,17B-triol (HI) was dissolved in 40 cc. of acetone and, while maintaining the interior temperature between 0 and C., 2.4 cc. of a sulfochromic acid solution were introduced. This solution was prepared from 0.416 gm. of chromic acid, 0.4 cc. of pure sulfuric acid and 4 cc. of distilled water.

The reaction mixture was allowed to stand next for a period of 3 hours under agitation at room temperature. Thereafter, it was taken up with water and extracted with methylene chloride. The extracts were washed with an aqueous solution of sodium bicarbonate, then with water, dried over sodium sulfate and concentrated to dryness under vacuum.

0.424 gm. of raw product was obtained which was dissolved in 4 cc. of methanol. The solution was concentrated to a volume of 2 cc. under an atmosphere of nitrogen and held overnight at 0 C.

The precipitate obtained was vacuum filtered, washed with methanol and dried under vacuum. 0.354 gm. of fl-allyl-A4-estrene-9a-ol-S,17-dione (IV) was obtained having a melting point of 200 C. and a specific rotation [a] =+135.5 (c.=0.5% in methanol). Yield: 81.5%.

This product is not described in the literature.

It occurs in the form of white prisms, soluble in acetone and chloroform, and insoluble in water, dilute aqueous acids and alkalis and isopropyl ether.

Analysis.C H O Molecular weight=328.43. Calculated: C, 76.79%; H, 8.59%. Found: C, 76.8%; H, 8.4%.

Step C-IOfl-allyl-A -estradiene-3,17-di0ne (V) 0.300 gm. of 1Ofl-allyl-A -estrene-9'u-ol-3,17-dione (IV) was dissolved in 35 cc. of anhydrous benzene and 1.2 gm. of pure zinc chloride were added thereto. The reaction mixture was heated to reflux for a period of 2 hours while agitating under an atmosphere of nitrogen. Thereafter, it was cooled to room temperature and taken up in suflicient water to dissolve the zinc chloride.

The solution was decanted and the aqueous phase extracted with methylene chloride. The organic phases were combined, washed with water, dried over sodium sulfate and evaporated to dryness under vacuum.

0.290 gm. of raw product was obtained which was taken up with 3 cc. of methylene chloride and passed through a column containing 30 gm. of magnesium silicate gel.

The column was eluted by a solution containing 1% of acetone in methylene chloride. The eluate was evaporated to dryness in a vacuum and 0.25 gm. of a product was obtained which was dissolved in 1 cc. of boiling isopropyl ether. The solution was allowed to stand overnight at 0? C. The precipitate was vacuum filtered, washed With isopropyl ether and dried under vacuum.

0.220 gm. of 10/8 allyl A -estradiene-3,17-dione (V) was obtained having a melting point of 120-121 C. and a specific rotation [u] ==+216 (c.=0.3% in ethanol). Yield: 78%.

The product occurred in the form of prismatic white crystals soluble in alcohol, benzene and chloroform, slightly soluble in isopropyl ether and insoluble in water, and dilute aqueous acids and alkalis.

Step D10fl-allyl A estradiene-Z 7,8-01-3-0212 (I, with R'=H).0.2 gm. of 10,8-ally1-A -estradiene- 3,17-dione (V) and 0.6 cc. of pyrrolidine were heated for a period of 15 minutes at C. under an atmosphere of nitrogen. The mixture was cooled to about +5 to +10 C. and 3 cc. of methanol were added. After holding the mixture 30 minutes at +5 C., the precipitate was vacuum filtered and washed with methanol, 3-pyrrolidy1- 10/3-a1lyl-A3 -estratriene-17-one was obtained.

0.100 of 3-pyrrolidyl-1OyS-ailyl-N -estratriene- 17-one in 5 cc. of dry ethyl ether, free of peroxides, was heated to reflux for a period of one hour with 0.100 gm. of lithium aluminum hydride. The reaction mixture was cooled, diluted with iced water and extracted with ethyl ether. The alumina was removed by filtering through diatom aceous earth. The extract was washed until neutral and distilled to dryness. 3-pyrrolidyl-10,6-allyl -estratriene-UB-ol was recovered.

3-pyrrolidyl-10paallyl-A -estratriene-17B 01 was hydrolyzed by heating to reflux for a period of 4 hours under nitrogen in a bath as follows:

Methanol oc 2 Acetic acid cc 0.2 Water ec 0.3 Sodium acetate Igm 0.3

The methanol was removed under vacuum. The product was diluted with water, extracted and the extract distilled to dryness.

10B-allyl-A -estradiene-17B-ol-3-one (I, with R=H) was obtained having a. melting point of 128-130 C. and a specific rotation [a] =+105 (c.-=0.5% in ethanol).

The product is soluble in. ethanol, acetone, benzene and chloroform, slightly soluble in ether and insoluble in water.

By esterification of 10/3-allyl-A -estradiene-1713-01- 3-one by means of a functional derivative of one of the acids enumerated above such as, for purposes of illustration only, the chloride of benzoic acid in the presence of a base, such as pyridine, the corresponding 17B-benzoyloxy-lOp-allyl-A -estradiene-3-or1e (I, with R=COC 'H was obtained. Obviously other esters of the acids enumerated above can be obtained by this or other known processes of esterification.

It is to be understood that the'invention is not limited to the specific examples described above. One canuse equivalent teohniques to the man skilled in the art without departing from the body of the invention or the scope of the appended claims.

We claim:

' 1. A process for the production of a IOB-allyl steroid of the formula v wherein R is selected trom the group consisting of hydrogen and the 'acyl radical of an organic oarhonylic acid having from one to eighteen carbon atoms which comprises the steps of reacting a compound of the formula a t3) triene-17-one to the action out a mixed metal hydride, hy-

drolyzing the 3-pyrrolidy1-10p-allyl-A -estnatriene- 17 6-01 by the action of an aqueous acidic solution and recovering said IOfi-allyl steroid.

' 2. The process of claim 1 wherein said allyl magnesium halide -is allyl magnesium hrorriide.

3. The process of producing l0B-allyl-A -estrene-3fi,9a, 17fl-triol which comprises the steps of reacting a compound of the formula wherein R is selected from the group consisting of hydrogen and the acyl radical of an organic carboxylic acid having from one to seven carbon atoms, with an allyl magnesium halide in an inert organic solvent, and recovering said 10,6aa1lyl-A -estrene-35,904,17B-triol.

4. The process of producing 10B-allyl-A -estradiene-3,17-dione which comprises the steps of dehydrating 1Ofi-allyl-A -estrene-9cool-3,l7-dione by the action of zinc chloride in an inert anhydrous organic solvent and recovering s-aid 10fi-ally1-A -estradiene-3,17-dione.

. 10B-ally1-A -estrene-35,90,17,8-triol.

10fi-allyl-M-estrene-9a-ol-3,l7-dione.

. 1OB-allyl-A -estradiene-3,17sdione.

. 3-pyrrolidyl-10,8-ally1-A -estratriene-17-one. 3-pyrrolidyl-10fl-a'llyl-A e -estratriene-lW-ol.

wooQpsut No references cited. 

1. A PROCESS FOR THE PRODUCTION OF A 10B-ALLYL STEROID OF THE FORMULA 